Opioid Overdose Case File

Opioid Overdose Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 60

A 21-year-old woman is brought into the emergency department by her college roommate. The patient has been unconscious for at least 30 minutes. The patient’s roommate is unaware of any health condition but states that the patient has attended several college parties over the last weeks, and though she is uncertain of this fact, she believes her roommate “has been doing drugs.” On examination, the patient is somewhat pale. Her mucous membranes are dry. Her temperature is 98 °F, heart rate is 80 beats per minute (bpm), respiratory rate is 8 breaths per minute, and blood pressure is 90/60 mm Hg. The skin has no lesions suggestive of intravenous injections. Her heart and lung examinations are unremarkable. The abdominal examination reveals hypoactive bowel sounds, and the abdomen is nontender. The patient barely opens her eyes upon painful stimulus. There is no evident focal deficit. Pupils are miotic and sluggish. There is a normal gag reflex. Routine laboratory tests are normal. The pregnancy test is negative. A urine drug screen is positive for opiates.

▶ What is the most likely diagnosis?

▶ What is the next step in therapy?

ANSWERS TO CASE 60:

Opioid Overdose

Summary: A 21-year-old woman presents with

• A history of possible drug misuse
• Stupor
• Normal gag reflex, cardiac and pulmonary examinations, and routine laboratory tests
• Hypoactive bowel sounds
• Bradypnea, hypotension, dry mucosa, and sluggish miotic pupils
• Positive urine drug screening for opiates

Most likely diagnosis: Opiate overdose.

Next step in therapy: Ensure airway, breathing, and circulation (ABC); administer naloxone, the antidote for opiates.

ANALYSIS

Objectives

1. Recognize the clinical characteristics of opiate overdose. (EPA 1)
2. Outline the differential diagnosis of stupor and coma. (EPA 2)
3. Compare the effect of opiates over the central nervous system with that of other drugs with potential for abuse. (EPA 1, 2)
4. Describe the sequence of interventions in the management of an emergent intoxication. (EPA 4, 10)

Considerations

This young woman presents stuporous with the reassuring presence of a gag reflex, which ensures that she is able to protect her airway. Her examination is nonspecific and shows sluggish miotic pupils. Her blood pressure is low, and her respiratory rate is slow. Her roommate says the patient “has been doing drugs,” and the drug screen is positive for opiates. While the differential diagnosis of stupor is broad, many signs point toward an acute opiate intoxication. Sadly, this patient’s presentation is all too common, since opioid use disorder has become an epidemic and is associated with a large number of deaths. The most important immediate intervention is respiratory support, since respiratory depression is the most common cause of death. Her oxygen saturation should be assessed, and ventilation should be provided using bag/mask for hypoxemia and/or a respiratory rate below 12/minute. Nalaxone, a competitive mu opioid receptor antagonist should be administered parenterally.

APPROACH TO:

Opiate Overdose

DEFINITIONS

COMA: A state in which an individual is unarousable and unresponsive.

DRUG ADDICTION: Neuropsychiatric disorder characterized by a recurring desire to continue taking the drug despite harmful consequences, or engagement in illegal or criminal activities in order to obtain access to such a drug.

OPIATE: A drug containing or derived from opium. It can be natural, semisynthetic, or synthetic.

STUPOR: A state between alertness and comatose, with an alert patient being arousable.

SUBSTANCE DEPENDENCE: Physiopharmacologic term that implies that the body has adapted to a substance, so its absence leads to some form of withdrawal syndrome.

SUBSTANCE USE DISORDER: According to the fifth edition of the Diagnostic Manual of Mental Disorders (DSM-5), it is defined as a problematic pattern of use of a substance leading to clinically significant impairment or distress, manifested within a 12-month period. The manifestations can include the following: strong urges; preoccupation with use; a reduction in social, occupational, or recreational activities; and more. Depending on the number of the diagnostic criteria met, a severity of mild, moderate, or severe is assigned.

CLINICAL APPROACH

Pathophysiology

Substance use disorder is a significant source of morbidity and mortality in the United States and throughout the world. Opioids continue to rise as a cause of drug overdoses, and an increasing amount of prescription opioids are involved. Due to this phenomenon, chronic opioid dependence to acute opioid toxicity as in this case are all part of the spectrum of pathology that can result from opioid use.

Opioids have central nervous system depressant and analgesic effects and can create a feeling of euphoria as well. The receptors for opioids are located in the central and peripheral nervous systems and include mu, kappa, and delta. Stimulation of mu receptors in the central nervous system results in responses such as respiratory depression, analgesia, euphoria, and miosis. Cough suppression and constipation can result from activation of peripheral mu-opioid receptors located in the smooth muscle of the bronchi and intestines, respectively.

Diagnosis. The history, physical examination, and routine and toxicologic laboratory evaluations are used to establish and confirm acute opioid toxicity. When approaching a stuporous patient, it is important to be methodical: Think first of the conditions for which an early diagnosis modifies the outcome. Such is the case for hypoglycemia, meningoencephalitis (needing a lumbar puncture), and some types of cerebrovascular accidents. As a rule of thumb, any other diagnosis allows clinicians to select tests appropriate to historical and exam-based features.

As soon as the patient presents, particularly if altered from an unknown drug, a rapid screening examination should be completed to determine if any immediate steps are needed to stabilize the patient. Vital signs should be measured, mental status should be assessed, and pupil size should be measured. Skin moisture should be assessed, and a thorough skin examination should be conducted to identify any stigmata of drug use (eg, needle tracks or presence of skin-based drug delivery such as a fentanyl patch). Pulse oximetry, continuous cardiac monitoring, and an electrocardiogram should be obtained. Intravenous access with large-bore catheters and a finger-stick blood glucose measurement should be obtained as well.

If unable to obtain a history from the patient, any information about known current medications or possible ingestion or substance consumed from a bystander or someone familiar with the patient would be helpful.

Differential Diagnosis. Table 60–1 offers a nonexhaustive differential diagnosis of stupor. A plethora of drugs that can result in stupor or coma need to be considered. Some of them cause distinct physical examination findings supporting alternative diagnoses. Antihistamines, antipsychotics, barbiturates, beta-adrenergic antagonists, carbon monoxide, cholinergics, clonidine, cyclic antidepressants, ethanol, toxic alcohols such as methanol or ethylene glycol, organophosphates and sympatholytics represent some examples of drugs that can impair the brain function.

Laboratory Tests. A finger-stick serum glucose concentration should be quickly obtained since hypoglycemia, which can be rapidly detected and corrected, may otherwise obfuscate the differential of opioid toxicity. All patients should have a urinalysis and serum chemistries evaluated, including electrolytes, blood urea nitrogen (BUN), creatinine, and glucose. Serum creatine kinase, liver function tests, lipase, ionized calcium, magnesium, arterial blood gas, serum osmolality, and serum lactate can also be tested. Urine pregnancy testing should always be obtained in any woman of childbearing age.

Some drug levels can be measured; such is the case of acetaminophen, alcohol, aspirin, and lithium. Salicylate concentration need not be obtained in the absence of elevated respiratory rate or high anion gap metabolic acidosis.

Other Tests. Other studies should be based on the known history and tailored to each patient’s presentation. This includes thyroid function tests, blood cultures, a chest x-ray, and brain imaging studies. An electrocardiogram may provide useful information, such as the duration of the QRS and QTc intervals, which could be modified by loperamide or methadone, respectively.

Special Considerations. A urine toxicologic screen is not always necessary but may be helpful. Acute opioid toxicity is a clinical diagnosis; importantly, if the clinical characteristics are present, the management of a patient with an opioid toxicity would not change if a urine opioid screen is negative. A positive test demonstrates recent use but does not confirm toxicity. Many opioids, especially the synthetic formulations, will produce a false-negative result in several available urine drug screens.

Clinical Presentation

The physical examination findings of opioid toxicity can include the following changes in vital signs: bradypnea, bradycardia, hypotension, and hypothermia. A common finding in opioid toxicity is respiratory depression. Hypoactive bowel sounds may be noted, and the patient may present comatose or with seizure. While miosis is characteristic, its absence or even the presence of mydriasis does not preclude opiate toxicity but could instead suggest co-ingestion of other drugs. The mental status of a patient presenting with opioid toxicity can range from euphoric to comatose.

Persistent immobility in the patient with stupor can lead to compressed fascia-bound muscle groups, resulting in compartment syndrome and rhabdomyolysis; the myoglobin released from injured muscle can precipitate in the renal tubules, leading to acute kidney injury.

Treatment

The initial management is focused on addressing the patient’s airway, breathing, and circulation and providing support to these systems if needed. Pulse oximetry may measure oxygenation but cannot determine the presence of hypercapnia. An arterial blood gas measurement may be needed.

The most significant therapeutic decision to make is the administration of naloxone; the success of this intervention also confirms the diagnosis of opioid toxicity. Naloxone is a short-acting opioid antagonist. It can be dosed starting at 0.04 mg intravenously; for patients presenting with apnea or cardiopulmonary arrest, at least 2 mg are usually necessary. Bradypneic patients should be ventilated by a bag valve mask attached to supplemental oxygen before and after naloxone administration to reduce the risk of acute respiratory distress syndrome. The dose should be increased every few minutes until the respiratory rate is 12 breaths/min or greater. The goal is to achieve adequate ventilation and not necessarily to normalize consciousness.

Naloxone can also be given intramuscularly, subcutaneously, or even intranasally if intravenous access cannot be obtained, but with these routes absorption is delayed and titration is difficult. As long as symptoms of opioid withdrawal are not present, more naloxone can be given, but after administration of 5 to 10 mg without a clinical response, the diagnosis should be reconsidered.

If opioid withdrawal occurs, the patient should be managed symptomatically and not by administration of more opioids. One important consideration in opioid toxicity as opposed to other drug toxicities is that activated charcoal and gastric emptying are never an appropriate management decision and are only considered if there is a strong suspicion for co-ingestion of other drugs.

Prevention. Most patients with acute opioid toxicity can be cared for in the emergency department without hospital admission, assuming there is no other medical issue of concern. Psychiatric evaluation can be done once respirations and mental status are normal. For patients with features consistent with addiction, rehabilitation is indicated. Teaching opioid users, family members, and friends how to recognize opioid toxicity and prescribing them naloxone reduces mortality.

Detoxification or supervised opioid withdrawal is the first step in treatment and reduces withdrawal symptoms. Medication is typically needed to prevent relapse. Naltrexone, which is an opioid antagonist, is a possible treatment, but it should be started after opioid withdrawal is thoroughly completed. Other treatments, such as methadone and buprenorphine, which are opioid agonists, can be started while a patient is still using opioids.

CASE CORRELATION

• See also Case 36 (Transient Ischemic Attack), Case 41 (Urinary Tract Infection With Sepsis in the Elderly), Case 43 (Meningitis, Bacterial), and Case 59 (Delirium/Alcohol Withdrawal).

COMPREHENSION QUESTIONS

60.1 A 59-year-old man with past medical history significant for long-standing hip and knee pain secondary to osteoarthritis is seen in clinic. The pain mildly improves with heat and relaxation, but he also has several acute exacerbations of pain daily that cause his “legs to freeze” and prevent him from working. These episodes do not respond to nonpharmacologic therapy, such as acupuncture. He has tried multiple nonopioid analgesic drugs but stopped them due to minimal improvement in pain or gastrointestinal side effects. Opioid therapy is considered. Which of the following is also recommended before prescribing opioid therapy to this patient?

A. Psychiatry referral

B. Current Opioid Misuse Measure survey

C. Naloxone prescription and education

D. Nonsteroidal anti-inflammatory therapies

E. Opioid-related harm risk factor assessment

60.2 A 29-year-old man with past medical history significant for heroin use is evaluated in the emergency department for stupor. On arrival, he was minimally responsive with miotic and sluggish pupils. He had needle tracks on his arms. His respiration rate was 8 breaths/min, but 5 minutes after administration of two doses of intravenous naloxone, his respiration rate is 16 breaths/min, and he is alert but not completely oriented. He does not remember what happened before the admission but is able to answer some questions. His vital signs have normalized. Which of the following is the best next step?

A. Discharge now with outpatient follow-up

B. Administer regular doses of naloxone starting now

C. Continue to observe for several hours

D. Elective endotracheal tube placement now

E. Gastric lavage now

60.3 A 37-year-old woman is brought into the emergency department by emergency medical services. The patient has been unconscious for at least 30 minutes and was found in a park. On examination, the patient is pale. Her mucous membranes are dry. Her temperature is 98 °F, heart rate 100 bpm, respiratory rate 10 breaths/min, and blood pressure 95/65 mm Hg. The skin has no lesions suggestive of intravenous injections. Her heart and lung examinations are unremarkable. The abdominal examination reveals hypoactive bowel sounds, and the abdomen is nontender. The patient barely opens her eyes upon painful stimulus. There is no evident focal deficit. Pupils are normal. There is a normal gag reflex. Routine laboratory tests are normal. The pregnancy test is negative. A urine drug screening is negative for opiates. What is the next best step in management?

A. Evaluate serum chemistries to evaluate anion gap

B. Assess serum osmolarity

C. Draw an ethanol level

D. Evaluate carboxyhemoglobin

E. Perform gastric lavage

F. Administer naloxone

60.4 A 34-year-old man with past medical history significant for the use of multiple illicit drugs is evaluated in the emergency department for impaired mentation. On arrival, he was minimally responsive with miotic and sluggish pupils. His respiration rate on arrival was 8 breaths/min, but 10 minutes after administration of three doses of intravenous naloxone, his respiration rate is 16 breaths/min, and he is alert and oriented and completely conversant. His vital signs are normal now, and his pulse oximetry demonstrates 99% on room air. He says that he would like to go home today, and he wants to completely stay away from drugs and be rid of this addiction. Which of the following is the best step in management?

A. Refer to psychiatry

B. Admit to the hospital

C. Discharge and refer to an opioid detoxification program

D. Administer naloxone

ANSWERS

60.1 E. Opioid therapy is reasonable in a patient with pain unresponsive to nonpharmacologic and nonopioid therapies. A treatment plan may include other therapies, such as cognitive behavioral therapy or physical therapy. If the risks outweigh the benefits and yet opiates are indicated, providers can offer a prescription for naloxone (answer C). Factors that increase risk for opioid overdose are history of overdose, history of substance use disorder, higher opioid dosages, and concomitant use of benzodiazepines. The presence of  chronic obstructive pulmonary disease (COPD) or obstructive sleep apnea should also encourage naloxone prescription. However, this would only be done after risk factor assessment. If the patient does not have an apparent mental health diagnosis, psychiatry referral (answer A) is not necessary before prescribing opioid therapy. Nonsteroidal therapies (answer D) have been ineffective in the past, and prescribing them again does not address the patient’s concerns. The Current Opioid Misuse Measure (answer B) is a self-report survey of current drug-related behavior meant for patients currently receiving long-term opioid therapy with possible misuse.

60.2 C. In the treatment of opioid overdose, naloxone therapy should be titrated to respiratory rate and not normalized mentation. This patient’s respiratory rate has recovered to greater than 12 breaths/min, but his mentation has not fully recovered. The antidote effects of naloxone will usually wear off before the opioid effects are eliminated. Thus, observation and repeated dosing depending on the clinical status may be necessary. The most crucial aspect to be wary of is respiratory depression. Discharging the patient now (answer A) would be inappropriate. Serial escalating doses of naloxone (answer B) may be necessary in some patients, and those patients may require a continuous naloxone infusion. However, it is not indicated in this patient at this time. Since breathing has normalized and the patient is protecting his airway, there is no indication for intubation (answer D). Gastric lavage (answer E) is never indicated in these patients unless there is a strong suspicion for co-ingestion of a substance for which such intervention has been proven useful.

60.3 F. When comparing the effects of opiates with that of other drugs with potential for abuse, it is helpful to begin the approach with whether the patient is in a state of physiologic excitation versus depression. There is more evidence here of physiologic depression. Physiologic depression can manifest as central nervous system depression, hypotension, bradycardia, bradypnea, and hypothermia; these symptoms are associated with opiates, ethanol cholinergics, sympatholytics, and toxic alcohols. Mixed effects can occur in many patients, and considerations of physical examination findings outside the central nervous system and vital signs can be helpful to elicit the diagnosis. They include body odors, pupillary findings, skin findings, and neuromuscular aberrations.

Normal pupillary findings do not rule out opiate toxicity. Urine toxicology screen may also be negative, particularly with synthetic opioids, and does not rule out the diagnosis. The most specific finding in this patient for possible opiate toxicity is the respiratory rate depression, and the quickest therapeutic decision that can be made here is administration of naloxone. Obtaining serum chemistries (answer A) or osmolarity (answer B) would be appropriate only after naloxone administration. Gastric lavage (answer E) is not indicated unless evaluation suggests another toxic ingestion and naloxone is ineffective. The ethanol level (answer C) may be checked but neither rules in nor excludes ethanol-related toxicity. Evaluation of carboxyhemoglobin (answer D) may be warranted due to unknown history, but it should be measured only after naloxone administration.

60.4 C. Opioid use disorder is a significant source of morbidity and mortality in the United States and throughout the world. The patient’s recognition of the drug burden on his life and desire to get over this drug use disorder should not be taken lightly. Detoxification or supervised opioid withdrawal is the first step in treatment and reduces withdrawal symptoms. Most patients with opioid toxicity can be cared for in the emergency department without hospital admission (answer B), assuming there is no other medical issue of sufficient concern. Psychiatric evaluation (answer A) may be needed if the patient’s history and presentation are consistent with indication for referral, but there is no such indicator in this patient. Teaching opioid users how to recognize opioid toxicity and giving them naloxone reduces mortality and may be beneficial to give to the patient upon discharge, but naloxone administration (answer D) does not need to be repeated now. Medication is typically needed to prevent relapse.

CLINICAL PEARLS

▶ The typical signs of acute opioid intoxication are central nervous system depression, bradypnea (especially < 12 breaths/minute), bradycardia, hypotension, decreased bowel sounds, and miotic pupils.

▶ A normal pupil examination does NOT exclude opioid toxicity.

▶ In stuporous patients, a finger-stick serum glucose concentration should be quickly obtained, as hypoglycemia can be rapidly detected and corrected.

▶ Electrocardiographic findings may provide useful information; the duration of the QRS and QTc intervals should be carefully noted.

▶ The initial management when opioid toxicity is suspected is addressing the patient’s airway, breathing, and circulation.

▶ If opioid toxicity is suspected, treat with the short-acting opioid antagonist naloxone, preferably intravenously.

▶ Normal mentation is not the goal, but rather a respiratory rate of 12 breaths/min or greater. Titrate the naloxone dose up and frequently until this goal is achieved.

▶ Opioid withdrawal symptoms should be managed symptomatically and not with more opioids.

▶ Activated charcoal and gastric emptying are not appropriate in acute opioid intoxication unless there is a strong suspicion for co-ingestion of other drugs for which these measures are indicated.

REFERENCES

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5). 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 

Baconi DL, Ciobanu AM, Vlasceanu AM, Cobani OD, Negrei C. Current concepts on drug abuse and dependence. J Mind Med Sci. 2015;(2):19-33. 

Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012;367(2):146-155. 

Doyon S, Aks SE, Schaeffer S. Expanding access to naloxone in the United States. J Med Toxicol. 2014;10(4):431-434. 

Hoffman JR, Schriger DL, Luo JS. The empiric use of naloxone in patients with altered mental status: a reappraisal. Ann Emerg Med. 1991;20(3):246-252. 

Mccaig LF, Burt CW. Poisoning-related visits to emergency departments in the United States, 1993–1996. J Toxicol Clin Toxicol. 1999;37(7):817-826. 

Osterwalder JJ. Naloxone—for intoxications with intravenous heroin and heroin mixtures—harmless or hazardous? A prospective clinical study. J Toxicol Clin Toxicol. 1996;34(4):409-416. 

Plum F, Posner JB. The Diagnosis of Stupor and Coma. 4th ed. Philadelphia, PA: Davis; 1995.

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